TMPRSS2

Chr 21

transmembrane serine protease 2

Also known as: PRSS10

NCBI Gene: 7113 ENSG00000184012 UniProt: O15393 OMIM: 602060

This protein is a plasma membrane-anchored serine protease that cleaves proteins at arginine residues and participates in proteolytic cascades important for normal prostate function. The gene is extremely tolerant to loss-of-function variants (very low constraint), and no Mendelian diseases have been definitively associated with TMPRSS2 mutations in pediatric populations. While the protein facilitates viral entry including SARS-CoV-2 and influences prostate cancer progression, these are not monogenic pediatric neurogenetic conditions.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a protein that belongs to the serine protease family. The encoded protein contains a type II transmembrane domain, a receptor class A domain, a scavenger receptor cysteine-rich domain and a protease domain. Serine proteases are known to be involved in many physiological and pathological processes. This gene was demonstrated to be up-regulated by androgenic hormones in prostate cancer cells and down-regulated in androgen-independent prostate cancer tissue. The protease domain of this protein is thought to be cleaved and secreted into cell media after autocleavage. This protein also facilitates entry of viruses into host cells by proteolytically cleaving and activating viral envelope glycoproteins. Viruses found to use this protein for cell entry include Influenza virus and the human coronaviruses HCoV-229E, MERS-CoV, SARS-CoV and SARS-CoV-2 (COVID-19 virus). Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2020]

OMIM ResearchGenerating clinical summary…

Active trials

385

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.94

LOEUF

Multiple*

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.94LOEUF

pLI 0.000

Z-score 1.81

OE 0.65 (0.46–0.94)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.40Z-score

OE missense 0.94 (0.85–1.03)

303 obs / 323.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.65 (0.46–0.94)

0≤0.351.4

Missense OE?0.94 (0.85–1.03)

0≤0.61.4

Synonymous OE?0.92

0≤1.21.6

LoF obs/exp: 20 / 30.9Missense obs/exp: 303 / 323.2Syn Z: 0.76

Background carrier burden — how many people carry a rare variant somewhere in TMPRSS2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 76

762 rare PASS variants

Rare truncating (LoF)

1 in 1,100

129 rare PASS variants

Rare synonymous (reference)

1 in 110

296 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for TMPRSS2. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 100	1 in 1,400
South Asian	~43k	1 in 54	1 in 740
Remaining (unassigned)	~30k	1 in 56	1 in 2,000
European (Finnish)	~27k	1 in 260	≈ 1 in 13,000
Admixed American	~22k	1 in 87	1 in 2,800
African / African American	~21k	1 in 62	1 in 490
East Asian	~20k	1 in 84	1 in 2,800
Ashkenazi Jewish	~13k	1 in 320	1 in 1,500
Middle Eastern	~2,884	1 in 66	≈ 1 in 2,900

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 13 of 13 coding exons well covered in gnomAD exomes. Genomes: 12 of 13 (exon 8 below).? see exons ↓

ClinVar Variant Classifications

0 submitted variants in ClinVar

ClinVar

Protein Context — Lollipop Plot

TMPRSS2 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

External Resources

Links to major genomics databases and tools

Franklin by Genoox

AI-powered variant curation and clinical analysis

DECIPHER

Genomic variants and phenotypes in rare disease patients

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

Prostate Cancer

The Predictive Value of Coexisting TMPRSS2-ERG Gene Fusion and PTEN Deletion in Prostate Cancer Patients with Biochemical Failure Status Post Salvage or Radical Radiation Therapy

RECRUITING

NCT02573636Sir Mortimer B. Davis - Jewish General HospitalStarted 2016-03

Clinical Literature

Open Research Assistant →

Landmark / reviewRecent case evidence

Key Publications

Landmark & review papers · by relevance

PubMed

SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor.

Hoffmann M et al.·Cell

2020

Fighting COVID-19.